X-21856627-A-G

Variant names:

• chrX-21856627-A-G
• rs765612557
• NM_206923.4:c.143A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_206923.4(YY2):​c.143A>G​(p.Asn48Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,210,176 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 0 hem.)
• Consequence: YY2 NM_206923.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.740
• Publications: 1 publications found

Genes affected

YY2 (HGNC:31684): (YY2 transcription factor) The protein encoded by this gene is a transcription factor that includes several Kruppel-like zinc fingers in its C-terminal region. It possesses both activation and repression domains, and it can therefore have both positive and negative effects on the transcription of target genes. This gene has an intronless coding region, and it appears to have arisen by retrotransposition of the related YY1 transcription factor gene, which is located on chromosome 14. [provided by RefSeq, May 2010]

MBTPS2 (HGNC:15455): (membrane bound transcription factor peptidase, site 2) This gene encodes a intramembrane zinc metalloprotease, which is essential in development. This protease functions in the signal protein activation involved in sterol control of transcription and the ER stress response. Mutations in this gene have been associated with ichthyosis follicularis with atrichia and photophobia (IFAP syndrome); IFAP syndrome has been quantitatively linked to a reduction in cholesterol homeostasis and ER stress response.[provided by RefSeq, Aug 2009]

MBTPS2 Gene-Disease associations (from GenCC):

• IFAP syndrome 1, with or without BRESHECK syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• keratosis follicularis spinulosa decalvans

  Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Olmsted syndrome, X-linked

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics
• osteogenesis imperfecta, type 19

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mutilating palmoplantar keratoderma with periorificial keratotic plaques

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• BRESEK syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• keratosis follicularis spinulosa decalvans, X-linked

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017691791).
• BP6: Variant X-21856627-A-G is Benign according to our data. Variant chrX-21856627-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3471890.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206923.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YY2	NM_206923.4	MANE Select	c.143A>G	p.Asn48Ser	missense	Exon 1 of 1	NP_996806.2	O15391
	MBTPS2	NM_015884.4	MANE Select	c.670+3124A>G		intron	N/A	NP_056968.1	O43462

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	YY2	ENST00000429584.3	TSL:6 MANE Select	c.143A>G	p.Asn48Ser	missense	Exon 1 of 1	ENSP00000389381.2	O15391
	MBTPS2	ENST00000379484.10	TSL:1 MANE Select	c.670+3124A>G		intron	N/A	ENSP00000368798.5	O43462
	MBTPS2	ENST00000365779.2	TSL:1	c.670+3124A>G		intron	N/A	ENSP00000368796.1	B9ZVQ3

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111888 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183409 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1098236 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363594

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30206

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40505

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842145

Other (OTH) AF: 0.0000217 AC: 1 AN: 46098

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111940 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34132

African (AFR) AF: 0.00 AC: 0 AN: 30825

American (AMR) AF: 0.00 AC: 0 AN: 10579

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3544

South Asian (SAS) AF: 0.000375 AC: 1 AN: 2666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53153

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	0.0010
DANN	Benign	0.50
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.74
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.034
Sift	Benign	0.70	T
Sift4G	Benign	0.81	T
Polyphen		0.0020	B
Vest4		0.0080
MutPred		0.24		Gain of disorder (P = 0.0876)
MVP		0.48
MPC		0.37
ClinPred		0.026	T
GERP RS		-3.5
Varity_R		0.022
gMVP		0.11
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765612557; hg19: chrX-21874745;